Monocytes are considered to be precursor cells of the mononuclear phagocytic system, and macrophages are one of the leading members of this cellular system. Macrophages play highly diverse roles in maintaining an organism’s integrity by either directly participating in pathogen elimination or repairing tissue under sterile inflammatory conditions. There are different subpopulations of macrophages and each one has its own characteristics and functions. In this review, we summarize present knowledge on the polarization of macrophages that allows the generation of subpopulations called classically activated macrophages or M1 and alternative activated macrophages or M2. Furthermore, there are macrophages that their origin and characterization still remain unclear but have been involved as main players in some human pathologies. Thus, we also review three other categories of macrophages: tumor-associated macrophages, CD169+ macrophages, and the recently named TCR+ macrophages. Based on the literature, we provide information on the molecular characterization of these macrophage subpopulations and their specific involvement in several human pathologies such as cancer, infectious diseases, obesity, and asthma. The refined characterization of the macrophage subpopulations can be useful in designing new strategies, supplementing those already established for the treatment of diseases using macrophages as a therapeutic target.

IntroductionThe interleukin-1 (IL-1) family of cytokines comprises 11 members, including IL-1␣, IL-1␤, IL-18, IL-33, and the recently renamed IL-36␣, ␤, ␥ (previously known as IL-1F6, IL-1F8, and IL-1F9). 1 All these cytokines use heterodimeric receptors for signaling. IL-1, IL-33, and IL-36 bind to specific receptor ␣-chains, which are IL-1RI for IL-1␣ and IL-1␤, T1/ST2 (also known as IL-33R) for IL-33, and IL-36R (previously termed IL-1Rrp2) for IL-36, and then recruit the same coreceptor IL-1R accessory protein (IL-1RAcP). IL-18 uses IL-18R␣ and the coreceptor IL-18R␤. On receptor binding, all IL-1 family cytokines activate similar intracellular signals, including NF-B and mitogenactivated protein kinase (MAPK) pathways. IL-1 receptor antagonist (IL-1Ra) and IL-36Ra (previously termed IL-1F5), 2 additional members of the IL-1 family, act as natural inhibitors for the biologic activities of IL-1 and IL-36, respectively. [2][3][4] IL-1␣, IL-1␤, IL-18, and IL-33 are produced by activated innate immune cells (neutrophils, monocytes, macrophages, and dendritic cells) and epithelial cells, and stimulate proinflammatory innate and adaptive immune responses. More specifically, these cytokines influence CD4 ϩ T-cell responses and their polarization into the different T helper (Th) subsets Th1, Th2, and Th17. IL-1 promotes the proliferation and survival of naive CD4 ϩ T cells and plays a critical role in Th17 differentiation. 5-9 IL-18 and IL-33 stimulate the polarization of CD4 ϩ T cells into Th1 and Th2, respectively,10 although the selectivity of these responses may be modulated by the cytokine environment. Consistently, Th1, Th2, and Th17 cells selectively express the IL-1 family cytokine receptors IL-18R␣, T1/ST2, and IL-1RI, respectively. 10 IL-36 cytokines and IL-36R are abundantly expressed by keratinocytes and other epithelial cell types. 4,[11][12][13] IL-36 plays a major role in mouse experimental skin inflammation and in human psoriasis both in the initiation and regulation of inflammatory responses. [14][15][16][17][18][19] Furthermore, the association of a form of generalized pustular psoriasis with genetic IL-36Ra deficiency in humans argues in favor of a significant role of IL-36 in inflammatory skin diseases. 20,21 Recently, we have shown that dendritic cells (DCs) express IL-36R and that IL-36 stimulates the production of several cytokines and enhances the expression of costimulatory molecules in bone marrow-derived DCs (BMDCs). The stimulatory effects of IL-36 were more robust than those of the other members of the IL-1 family. In addition, IL-36 stimulated the production of interferon ␥ (IFN-␥), IL-4, and to a lesser extent IL-17 by cultured splenocytes and activated CD4 ϩ T cells, and IL-36 was able to act as an adjuvant to stimulate Th1 responses in vivo. 22 In the results described herein we show that, among CD4 ϩ T-cell subsets, IL-36R is predominantly expressed by naive CD4 ϩ T (referred to also as naive Th) cells and that IL-36 stimulates activated naive CD4 ϩ T (referred to also as Th0) cell ...

The contribution of a transmembrane (Tm) form of TNF to protective immunity against Mycobacterium bovis bacillus Calmette-Guérin (BCG) was studied in transgenic (tg) mice expressing a noncleavable Tm TNF but lacking the TNF/lymphotoxin-α (LT-α) locus (Tm TNF tg mice). These mice were as resistant to BCG infection as wild-type mice, whereas TNF/LT-α−/−, TNF−/−, and LT-α−/− mice succumbed. Tm TNF tg mice developed granulomas of smaller size but at 2- to 4-fold increased frequencies compared with wild-type mice. Granulomas were mainly formed by monocytes and activated macrophages expressing Tm TNF mRNA and accumulating acid phosphatase. NO synthase 2 activation as a key macrophage bactericidal mechanism was low during the acute phase of infection in Tm TNF tg mice but was still sufficient to limit bacterial growth and increased in late infection. While infection with virulent Mycobacterium tuberculosis resulted in very rapid death of TNF/LT-α−/− mice, it also resulted in survival of Tm TNF tg mice which presented an increase in the number of CFU in spleen (5-fold) and lungs (10-fold) as compared with bacterial load of wild-type mice. In conclusion, the Tm form of TNF induces an efficient cell-mediated immunity and total resistance against BCG even in the absence of LT-α and secreted TNF. However, Tm TNF-mediated protection against virulent M. tuberculosis infection can also be efficient but not as strong as in BCG infection, in which cognate cellular interactions may play a more predominant role in providing long-term surveillance and containment of BCG-infected macrophages.

SUMMARY:The role of nitric oxide (NO) in Mycobacterium bovis Bacillus Calmette Gué rin (BCG) infection was investigated using nitric oxide synthase 2 (nos2)-deficient mice, because NO plays a pivotal protective role in M. tuberculosis infection. We demonstrate that nos2-deficient mice were unable to eliminate BCG and succumbed within 8 to 12 weeks to BCG infection (10 6 CFU) with cachexia and pneumonia, whereas all infected wild-type mice survived. The greatest mycobacterial loads were observed in lung and spleen. Nos2-deficient mice developed large granulomas consisting of macrophages and activated T cells and caseous necrotic lesions in spleen. The macrophages in granulomas from nos2-deficient mice had reduced acid phosphatase activities, suggesting that NO is required for macrophage activation. The absence of NOS2 affected the cytokine production of the Th1 type of immune response, except IL-18. Serum amounts of IL-12p40 were increased and IFN-␥ was decreased compared with wild-type mice. The lack of NOS2 resulted in an overproduction of TNF, observed throughout the infection period. Additionally, TNFR1 and TNFR2 shedding was altered compared with wild-type mice. Up-regulation of TNF may be compensatory for the lack of NOS2. The late neutralization of TNF by soluble TNF receptors resulted in heightened disease severity and accelerated death in nos2-deficient mice but had no effect in wild-type mice. In conclusion, the inability of nos2-deficient mice to kill M. bovis BCG resulted in an accumulation of mycobacteria with a dramatic activation of the immune system and overproduction of pro-inflammatory cytokines, which resulted in death. (Lab Invest 2000, 80:1385-1397.

Signaling via TNF receptor type 1 (TNFR1) was shown to be crucial in host defense against the intracellular pathogens L. monocytogenes, M. tuberculosis and M. bovis. Toinvestigate the function of TNF and LTα  in host defense against M. bovis, mice double deficient for TNF and LTα  (TNF / LTα – / –), TNF / LTα – / – mice complemented with a murine LTα  transgene (TNF– / –) and LTα – / – mice were infected with BCG and the ensuing pathology was investigated. Control mice showed a normal host defense with early clearance of bacteria. The granulomatous reaction in the liver was accompanied by recruitment of activated macrophages characterized by their acid phosphatase positivity and differentiation into epithelioid cells as well as a coordinated expression of proinflammatory transcripts. In contrast, TNF / LTα – / – mice showed no comparable recruitment of activated macrophages in the liver. Furthermore, these mice showed extensive necrotic pulmonary lesions with massive growth of acid fast bacilli. Reintroduction of LTα  as a transgene into TNF / LTα – / – mice prolonged survival but did not restore resistance to BCG. This, at least partially protective role of LTα  was further supported by data demonstrating that LTα ‐deficient mice as well were susceptible to BCG infection. In contrast to the deleterious effect of TNF / LTα  deficiency in BCG infection, BCG‐infected TNF / LTα – / – mice were tolerant to LPS‐induced shock. These results demonstrate that TNF as well as LTα  are involved in murine host defense against BCG and that absence of TNF / LTα  protects BCG‐infected mice from LPS mediated shock.