Innate Immune Responses to Lung-Stage Helminth Infection Induce Alternatively Activated Alveolar Macrophages

Abstract

While it is well established that infection with the rodent hookworm Nippostrongylus brasiliensis induces a strongly polarized Th2 immune response, little is known about the innate host-parasite interactions that lead to the development of this robust Th2 immunity. We exploited the transient pulmonary phase of N. brasiliensis development to study the innate immune responses induced by this helminth parasite in wild-type (WT) and severe-combined immune deficient (SCID) BALB/c mice. Histological analysis demonstrated that the cellular infiltrates caused by N. brasiliensis transit through the lungs were quickly resolved in WT mice but not in SCID mice. Microarray-based gene expression analysis demonstrated that there was a rapid induction of genes encoding molecules that participate in innate immunity and in repair/remodeling during days 2 to 4 postinfection in the lungs of WT and SCID mice. Of particular note was the rapid upregulation in both WT and SCID mice of the genes encoding YM1, FIZZ1, and Arg1, indicating a role for alternatively activated macrophages (AAMs) in pulmonary innate immunity. Immunohistochemistry revealed that nearly all alveolar macrophages became YM1-producing AAMs as early as day 2 postinfection. While the innate responses induced during the lung phase of N. brasiliensis infection were similar in complexity and magnitude in WT and SCID mice, only mice with functional T cells were capable of maintaining elevated levels of gene expression beyond the innate window of reactivity. The induction of alternatively activated alveolar macrophages could be important for dampening the level of inflammation in the lungs and contribute to the long-term decrease in pulmonary inflammation that has been associated with helminth infections.The cells and molecules that comprise the innate immune responses are the first line of defense against invading pathogenic organisms. In addition, innate immune mechanisms are important for the elimination of the myriad of nonpathogenic substances to which we are continuously exposed. In those circumstances in which the effector mechanisms of the innate response are not sufficient to fully eliminate a pathogen challenge, the same cells and molecules function to efficiently activate the antigen-specific adaptive arm of the immune response. In recent years, it has become clear that different modes of activation of innate immunity have a profound influence on the magnitude and the nature of subsequent adaptive responses (9,32,69).Parasitic nematodes are among the strongest natural inducers of polarized Th2 immune responses (2, 40, 60). Infection of mice with the intestinal nematode parasite Nippostrongylus brasiliensis has been used extensively to study the regulation of immunoglobulin E synthesis (31) and Th2 immunity in general (19,33). Despite the longstanding use of N. brasiliensis as a model, little is known about the innate immune responses that precede the induction of a highly polarized adaptive Th2 response to N. brasiliensis challenge. Indeed, there are only limite...

Nippostrongylus brasiliensis infection leads to the development of emphysema associated with the induction of alternatively activated macrophages

“…day 70+). These data are at odds to the conclusions drawn by Reece et al [19], who reported that mechanical damage and hemorrhaging are rapidly resolved following Nb infection. Indeed, the early innate response and massive hemorrhaging that occurs immediately following Nb infection is largely resolved within 12 days, however, they did not examine later time points.…”

“…Alternative macrophage activation is driven primarily through the presence of IL-4 although IL-13 and IL-21 have also been implicated in their differentiation [20,21]. Infection by Nb induces a strong Th2 immune response and is known to activate alternative macrophages [19]; however, their long-term presence in the airways suggests that additional mechanisms flowing on from the original infection may sustain their renewal and differentiation. Notably, microarray analysis of lungs from smokeinduced emphysema [22] show a similar pattern of gene expression to that described here; specifically, the upregulation of alternatively activated macrophage markers including FIZZ, YM1, and AMcase and the protease MMP-12.…”

Alternatively activated macrophages in helminth infections

“…In contrast, rapid increases of AAMΦs are detected in the lung by 4 days after N. brasiliensis infection in SCID mice lacking T cells, and this increase is associated with elevated Ym1, FIZZ1/RELMα, and arginase-1. After day 4, however, expression of these genes decreases markedly in the lungs of N. brasiliensis-infected SCID but not in infected WT mice [4], suggesting that innate cells may make sufficient IL-4/IL-13 to induce initial differentiation of AAMΦs, but that Th2 cells are required to sustain their activity. Mice infected with the cestode T. crassiceps and subsequently co-infected with either of two protozoan species of Leishmania exhibit a potent Th2-type response without downregulating IFN-γ levels; nevertheless, the protective response to Leishmania is blocked and disease exacerbated.…”

“…AAMΦs are observed in a variety of helminth infections, including Th2-type immune responses to Schistosoma mansoni [2], Heligmosomoides polygyrus [3], Nippostrongylus brasiliensis [4], Taenia crassiceps [5], Trichinella spiralis [6], Fasciola hepatica [7], Ascaris suum [8], and filarial parasites [9]. A number of markers are used to identify AAMΦs ( Figure 1).…”

Dynamics of lung macrophage activation in response to helminth infection

“…Surgeries were performed as described previously [13]. In short, animals were anesthetized with 300 mg/kg body weight with Avertin (2,2,2-tribromoethanol, Acros Organics, Morris Plains, NJ, USA), administered i.p.…”