IL-33 And M2A Alveolar Macrophages Promote Lung Defense Against The Atypical Fungal Pathogen Pneumocystis Murina

Abstract

We have recently reported that mice deficient in the myeloid Src-family tyrosine kinases Hck, Fgr, and Lyn (Src triple knockout [TKO]) had augmented innate lung clearance of Pneumocystis murina that correlated with a higher ability of alveolar macrophages (AMs) from these mice to kill P. murina. In this article, we show that despite possessing enhanced killing, AMs from naive Src TKO mice did not demonstrate enhanced inflammatory responses to P. murina. We subsequently discovered that both AMs and lungs from P. murina-infected Src TKO mice expressed significantly greater levels of the M2a markers RELM-α and Arg1, and the M2a-associated chemokines CCL17 and CCL22 than did wild-type mice. IL-4 and IL-13, the primary cytokines that promote M2a polarization, were not differentially produced in the lungs between wild-type and Src TKO mice. P. murina infection in Src TKO mice resulted in enhanced lung production of the novel IL-1 family cytokine IL-33. Immunohistochemical analysis of IL-33 in lung tissue revealed localization predominantly in the nucleus of alveolar epithelial cells. We further demonstrate that experimental polarization of naive AMs to M2a resulted in more efficient killing of P. murina compared with untreated AMs, which was further enhanced by the addition of IL-33. Administration of IL-33 to C57BL/6 mice increased lung RELM-α and CCL17 levels, and enhanced clearance of P. murina, despite having no effect on the cellular composition of the lungs. Collectively, these results indicate that M2a AMs are potent effector cells against P. murina. Furthermore, enhancing M2a polarization may be an adjunctive therapy for the treatment of Pneumocystis. Pneumonia caused by NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptwere diagnosed in the year 2009, and 25,000 deaths (19,000 in 2002) were recorded as a result of HIV infection (2). Although the advent of highly active antiretroviral therapy (HAART) has decreased the overall incidence of Pneumocystis carinii pneumonia (3), the mortality rate of those requiring hospitalization remains high (3). A recent retrospective study in an academic medical center found that overall hospital mortality rate to P. jiroveci pneumonia was 11.6%, and in those patients requiring intensive care, 29.0% (4). An additional study summarized the experience with HIV-associated P. carinii pneumonia over a 21-y period in a single center and found that mortality was 10.1% for the period from 1985 through 1989, 16.9% for the period from 1990 through June 1996, and 9.7% for the period from July 1996 through 2006 (i.e., the HAART era) (5). A major concern voiced by this study is the similar mortality associated with P. jiroveci pneumonia pre-and post-HAART.It is widely reported that phagocytosis by alveolar macrophages (AMs) is the predominant mechanism of Pneumocystis murina clearance from the lungs (6-8); however, the mechanisms by which macrophages kill P. murina are not completely understood. It is hypothesized that on phagocytosis, the oxidative burst b...

ExperimentalPneumocystislung infection promotes M2a alveolar macrophage-derived MMP12 production

“…Results in Fig. 3A show that Src TKO mice had increased Mmp12 expression in the lungs 7 days after P. murina lung challenge, a time point at which M2 signature genes are increased (28). It is important to note that Src TKO mice had enhanced Mmp12 expression by day 7, which is a week earlier than wild-type control mice express significant Mmp12 in the lungs (Fig.…”

“…We have recently reported that macrophage activation during P. murina lung infection in resistant mice favors alternative macrophage activation (28). Although MMP12 expression may be associated with alternative macrophage activation (14), data also support a role for IFN-␥ in the induction of MMP12 (10,19).…”

“…We have previously reported that mice deficient in the myeloid Src family kinases Hck, Fgr, and Lyn (Src TKO mice) demonstrated an increase in alternatively activated macrophages (28), which we have demonstrated to have an enhanced capacity to kill P. murina (28,29). Because Src TKO mice are more resistant to P. murina lung infection (29), we questioned whether this observation correlated with Mmp12 expression.…”

IL-33–Induced Hematopoietic Stem and Progenitor Cell Mobilization Depends upon CCR2

“…In Pneumocystis murina lung infection, IL-33 enhances the killing activity of macrophages (33). An IL-33-mediated reduction of Pseudomonas aeruginosa-induced corneal keratitis correlates with M2 macrophage polarization and the decrease in bacterial numbers in the cornea (34).…”

IL-33 Priming Regulates Multiple Steps of the Neutrophil-Mediated Anti-Candida albicans Response by Modulating TLR and Dectin-1 Signals

“…IL-33 acts on a variety of cells of the innate arm of immunity, including neutrophils, macrophages, dendritic cells, mast cells, basophils, and eosinophils, and functions as an amplifier of inflammation (5)(6)(7)(8)(9)(10)(11)(12)(13). Recent studies have suggested that IL-33 plays a role in infection-related inflammation, as IL-33 is protective against infection by opportunistic pathogens such as Pseudomonas aeruginosa, Pneumocystis murina, Cryptococcus neoformans, and polymicrobes (6,8,9,14). Prior to this study, there had been no publications regarding the role of IL-33 in Candida albicans infections.…”