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<p>Review Article </p> <p>Resident Tissue Leukocytes: Underappreciated Guards of the Body </p> <p>Department of Evolutionary Immunobiology, Jagiellonian University, ul. Ingardena 6, 30-060 Krakow, Poland Elzbieta Kolaczkowska </p> <p> Corresponding Author &amp; Address: </p> <p>Department of Evolutionary Immunobiology, Jagiellonian University, ul. Ingardena 6, 30-060 Krakow, Poland; Email: </p> <p>Elzbieta Kolaczkowska </p> <p> Published: 25th May, 2010 Accepted: 25th May, 2010 Received: 19th March, 2010 Revised: 12th May, 2010 Open Journal of Hematology, 2010, 1-1 Kolaczkowska E.; licensee Ross Science Publishers ROSS Open Access articles will be distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided that the original work will always be cited properly. In memory of Jacek Koaczkowski </p> <p>ABSTRACT </p> <p>Inflammatory reactions occurring in different milieu follow common phases with major highlights being local changes in vascular permeability and influx of inflammatory leukocytes that eliminate the source of inflammation while subsequent resolution is completed by tissue repair. The main inflammatory cells consist of blood-derived neutrophils and macrophages that arrive to the inflammatory site in response to a chemotactic signal. However, their arrival to the loci is initiated by a special set of leukocytes already present in various places of the body such as skin or body cavities that are called tissue or resident leukocytes. The cells consist of mast cells, macrophages and lymphocytes. Although the presence of resident leukocytes is commonly recognized their actual involvement in subsequent stages of inflammation is underappreciated while the cells are critical for all phases of the reaction. The current mini-review describes the role of resident leukocytes in the initiation, the course, and the termination of exemplary acute inflammatory reaction, namely zymosan-induced peritonitis. Additionally, facts on human resident peritoneal leukocytes are presented and discussed. </p> <p>Inflammation is universally defined as a reaction of the body to injury or infection of vascularized tissues with the purpose to deliver defensive materials, such as blood cells and fluid, to the site of injury/infection [1]. The traces of understanding of this process can be found dating back as far as 2700 B.C., and the four cardinal signs of inflammation (redness, swelling, heat and pain) were put in written form already in the first </p> <p>century A.D. by the physician Cornelius Celsus [1]. By now the mechanisms behind the signs of inflammation are generally known and many aspects of the inflammatory machinery are explained, yet not all. While the role of neutrophils and monocyte-derived macrophages newly infiltrating the sites of inflammation is well recognized and widely studied, the role of leukocytes residing in tissues prior to inflammation is often underestimated. This is </p> <p>Open Journal of Hematology OPEN ACCESS </p> <p></p> <p>Open Journal of Hematology, 2010, 1-1 Resident Tissue Leukocytes in Inflammation </p> <p>Page 2 of 16 (Page number not for citation purposes) </p> <p>especially inequitable as the cells are critical for the onset of the inflammatory reaction and, furthermore, play a significant role during the peak of the process and might have even impact on the resolution of the reaction. </p> <p>RESIDENT LEUKOCYTES: LYMPHOCYTES, MACROPHAGES AND MAST CELLS </p> <p>In certain vascularized tissues of the body that are exposed to the external environment such as skin, airways, gastrointestinal track, body cavities (e.g. pleural or peritoneal cavity) so called resident tissue leukocytes are located [1]. The cells migrate to the above tissues in physiological conditions and their function is to guard for any pathogens, allergens or other environmental agents (e.g. toxins) that might enter the body. Thus resident leukocytes provide the first line of cellular immune defense. Their composition and functions will be discussed on the example of peritoneal cavity that is located in the abdomen. Peritoneal cavity is a space between two layers of peritoneum that is the largest (with the area comparable to the skin) and most complexly arranged serous membrane of the body [2]. It contains a thin film of serous fluid, which is essentially an ultrafiltrate of plasma [3]. The fluid contains resident peritoneal leukocytes that in humans consist of approximately 70% macrophages, 10% B lymphocytes, 10% T lymphocytes, and 10% mast cells [4]. In mice the cellular composition is different with similar numbers of macrophages and lymphocytes (mostly B cells) and 2-4% of mast cells [5, 6]. The data on exact proportion of particular resident leukocyte populations in mice differs according to the applied identification methods e.g. detecting different surface markers of B cells (CD19, B220, CD5) [5-7]. However, there are clear strain differences in macrophage and B cell numbers e.g. peritoneum of Balb/c mice contains more B cells than macrophages in sharp contrast to NOD mice (the diabetes-prone strain) while other strains (e.g. C57Bl/6, CBA, CH/He, DBA1, NZW, MRL/Mp-Ipr) have similar numbers of both cell types [6]. </p> <p>B cells </p> <p>Peritoneal cavity is populated by rather unique B lymphocyte populations. Commonly B cells are divided into (i) evolutionary conservative </p> <p>B-1 cells rapidly producing T cell-independent low affinity antibodies, and (ii) more conventional (mostly follicular) B-2 cells producing T cell-dependent high affinity antibodies. In terms of surface phenotype they were initially showed to be CD5+ and CD5-, respectively [8]. However, the further studies of peritoneal cavity B cells revealed that at least some B-1 cells lack CD5 and for this B-1 cells were further subdivided into B-1a (CD5+B220+Mac-1+) and B-1b (CD5-B220+Mac-1+, sister cells) [9]. Therefore the phenotype criteria turned out not to be fundamental for distinguishing B-1 and B-2 cells. What further discriminates the two populations is their appearance in either fetal or adult life and for this it was recently proposed that the B cells that are readily generated from fetal/neonatal precursors (but poorly from adult precursors) are to be coined B-1 whereas the B cells generated throughout adult life - B-2 cells [10]. Peritoneal cavity is inhabited mostly by B-1 cells, however, B-2 cells are also present at this locus. Nevertheless, the peritoneal B-2 cells appear to be intermediate between splenic B-2 and peritoneal B-1b cells e.g. they require CD11b expression and ability to produce IgM antibodies as B-1 cells [11]. </p> <p>Fetal precursors of B-1 cells have unique characteristics such as lack of TdT (an enzyme responsible for inserting nucleotides to the VDJ exons during antibody gene recombination) and delayed expression of MHC II [10]. Moreover, the precise lineage restriction of early developing hemopoietic cells in fetal liver may differ from that in bone marrow and in fact a presence of novel B cell precursors was described. In particular, B/myeloid bipotential precursors were reported in fetal liver [12], but similar cells with a novel CD19+B220- phenotype were also detected in bone marrow [13]. In this regard this is not surprising that presence of biphenotypic CD5+B/macrophage cells was subsequently reported and until now in vivo they were observed only in peritoneum. The B/macrophage cells exhibit simultaneously characteristics of both B-1 lymphocytes (IgM, IgD, B220+, CD5+) and macrophages (phagocytosis, COX-1/COX-2, F4/80+, Mac-1+) [14, 15]. Their capacity to perform the most ancient defense mechanism phagocytosis combined with the ability to produce antibodies suggests their direct link to pre-lymphocytes that emerged some 400-500 million years ago in </p> <p>Open Journal of Hematology, 2010, 1-1 Resident Tissue Leukocytes in Inflammation </p> <p>Page 3 of 16 (Page number not for citation purposes) </p> <p>ancient vertebrates [16]. Although the exact role of B/macrophage cells was never fully explained it was shown that the cells release prostaglandins PGE2, PGF2 and PGD2 in a COX-2-dependent manner [15]. As PGD2 and its metabolites activate the nuclear receptor PPAR that regulates lipid </p> <p>metabolism, and PGE2 down-regulates IL-12 production, PGE2 synthesis by B/macrophage cells may shift the balance of an immune response towards Th2 and humoral immunity [15]. This, however, needs to be demonstrated empirically. </p> <p> Table 1. RESIDENT LEUKOCYTES PRESENT IN PERITONEUM OF MICE. numerous or few refer to contribution of a given subtype to the individual cell population (e.g. of B cells). </p> <p>Cell type Subtype Characteristic markers/products </p> <p>lym</p> <p>phoc</p> <p>ytes</p> <p>B cell B-1 (numerous) B220, Mac-1, CD11b, CD5 (some cells) untypical B-2 (few) CD23, production of IgM </p> <p>B cells/macrophages (few) B220, CD5, F4/80, Mac-1; production of IgM, IgD </p> <p> T cells </p> <p>T/ (numerous) / type of TCR, mostly with V6/V1 chains T natural helper cells = </p> <p>Th2-type innate lymphocytes (few) c-kit, Sca-1 (= Ly6a), production of Th2 cytokines (IL-5, IL-6, IL-13) </p> <p> Macrophages derived from Ly6C-CD62L- </p> <p>monocytes F4/80hi, Cd115low, CD62Llow, CD43low vs. inflammatory macrophages </p> <p>Mast cells CTMC = connective tissue mast cells </p> <p>production of heparinhi, histaminehi, leukotrieneslow vs. mucosal mast cells (MMC) </p> <p>Based on [6, 8, 9, 11, 14, 15, 17, 19, 29, 61, 62] </p> <p>T cells </p> <p>Apart of B cells, among lymphocytes present in peritoneum there are CD4+ Th cells, CD8+ Tc cells, CD4+CD25+ regulatory T cells and NK cells [5, 7]. From the point of view of a TCR type, gamma/delta TCR lymphocytes (T/) constitute an important division among peritoneal T cells [7, 17] and particularly the cells bearing invariant V6/V1 chains are present in peritoneum [18, 19]. This T cell subset differentiates in the thymus at the very early stage of ontogeny and bears truly </p> <p>invariant TCR without junctional diversity therefore T6/1 cells represent one of the most primitive cells participating in the first line immune response [19]. Just recently another unique T cell population was described in murine peritoneum Lin-c-kit+Sca-1+(Ly6a+) lymphoid cells. The cells are present in adipose tissue in peritoneum where they form a lymphoid structure (FALC, fat associated lymphoid cluster) [17]. The cells are distinct from lymphoid progenitors but IL-2-stimulated produce Th2 cytokines (IL-5, IL-6, IL-13) that regulate B-cell antibody production and sustain self-renewal of B-1 cells and IgA synthesis </p> <p>[17]. They were classified as Th2-type innate lymphocytes and are now called natural helper cells (Table 1). </p> <p>Macrophages </p> <p>There are two distinct peripheral blood monocyte subsets characterized by differential cell surface expression of chemokine receptors and adhesion molecules [6]. In mice Ly6C-CD62L- monocytes are precursors of resident macrophages that migrate to tissues in physiological conditions. In contrast, Ly6C+CD62L+ cells migrate to inflammatory sites upon antigen-induced chemotactic call [6]. In humans, these correspond to CD14+CD16+ and CD14++CD16-, respectively [6]. The numbers of the two monocyte subsets are very similar independently of mouse strain with the exception of NOD mice that have high counts of Ly6C-CD62L- cells and consequently much more peritoneal macrophages [20]; and furthermore, NOD mice have a profound defect in the recruitment of inflammatory macrophages [21]. The exactly opposite pattern is observed in Balb/c mice [20] thus the data from the two strains of mice confirmed that resident </p> <p>Open Journal of Hematology, 2010, 1-1 Resident Tissue Leukocytes in Inflammation </p> <p>Page 4 of 16 (Page number not for citation purposes) </p> <p>and inflammatory macrophages are derived from phenotypically and functionally different monocytes. This was further substantiated by an observation that LPS-stimulated resident peritoneal macrophages produce high levels of IL-6 and very low levels of IL-1 in sharp contrast to LPS-stimulated inflammatory macrophages induced by casein (one of the principal components of thioglycollate) [6]. The inflammatory macrophages are also slightly larger [6]. The two subsets of macrophages differ also in expression of some surface molecules as the resident cells express higher levels of 48/80 but lower of CD115, CD62L and CD43 than the inflammatory macrophages as shown in the latter case on thioglycollate-induced macrophages (Table 1) [6]. </p> <p>Moreover, there is diversity between resident peritoneal macrophages from various mouse strains with major differences detected in Balb/c mice. While expression of numerous macrophage surface molecules (CD11b, CD115, CD62L, CD43, Mac-3) is similar in different strains Balb/c mice are characterized by presence of numerous F4/80+ macrophages that are simultaneously expressing B220 (over 68% of the cells) which is considered to be a cell surface marker for B cells [6]. In contrast, in other investigated strains (C57Bl/6, CBA, CH/He, DBA1, NZW, MRL/Mp-Ipr) maximally 15% of peritoneal cells carry the F4/80+B220+ phenotype [6]. Although no further detailed studies were carried out on the double positive cells it cannot be excluded that these are related to biphenotypic B/macrophage cells described above. This would also correspond with the recognized dominance of the humoral immune response operating in Balb/c mice [22]. </p> <p>The secretory activity of resting resident peritoneal leukocytes is rather low and the major released protein is apoprotein E (ApoE) which is a ligand for low density lipoprotein receptors and thus participates in the transport of cholesterol and other lipids among various cells of the body [23]. The appearance of ApoE secretion correlates with the acquisition of mature macrophage phenotype, however, upon stimulation (e.g. with LPS or IFN-) resident macrophages limit the secretion of ApoE from app. 25% of total protein to &lt; 2% [23]. </p> <p>Interestingly, some features of resident peritoneal macrophages change with age. For example, the cells from senescent mice express higher basal levels of transglutaminase (one of the markers of macrophage activation) and show increased phagocytic activity of zymosan particles indicating that aging resident macrophages are more activated than those from young mice [24, 25]. However, when the cells were challenged by inflammation in vivo they were not capable of reaching the same levels of activation as macrophages from young animals. Moreover, the inflammatory senescent macrophages were not capable of coping with a second challenge [26]. Most likely this reflects age-related changes in some basic mechanism e.g. signal transduction and/or protein synthesis/degradation but also altered responsiveness to env...</p>


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