Enhanced protection to Mycobacterium tuberculosis infection in IL‐10‐deficient mice is accompanied by early and enhanced Th1 responses in the lung

Abstract

IL-10 regulates the balance of an immune response between pathogen clearance and immunopathology. We show here that Mycobacterium tuberculosis (Mtb) infection in the absence of IL-10 (IL-10−/− mice) results in reduced bacterial loads in the lung. This reduction was preceded by an accelerated and enhanced IFN-γ response in the lung, an increased influx of CD4+ T cells into the lung, and enhanced production of chemokines and cytokines, including CXCL10 and IL-17, in both the lung and the serum. Neutralization of IL-17 affected neither the enhanced production of CXCL10 nor the accumulation of IFN-γ-producing T cells in the lungs, but led to reduced numbers of granulocytes in the lung and reduced bacterial loads in the spleens of Mtb-infected mice. This suggests that IL-17 may contribute to dissemination of Mtb.

Pulmonary Mycobacterial Granuloma

“…11,12,[53][54][55][56][57] M. bovis BCG also uss similar immune evasion strategies as M.tb to dampen host immune activation mechanisms including intracellular persistence, 58 -60 inhibiting MHC molecule expression, 42,61 and inducing IL-10 production. [37][38][39]62 Despite these described similarities, we must caution that, compared with Immunosuppression of Bacterial Granuloma 1631 AJP April 2011, Vol. 178, No.…”

“…65 In a fashion similar to that of the tumor, although it is believed that mycobacteria may simultaneously use multiple mechanisms of immune evasion including mechanisms of down-regulating antigen presentation, 42,61 in the current study we have shown that IL-10 is one of the essential mechanisms through which the immune suppressive environment of mycobacterial granuloma is maintained. Despite the overwhelming evidence to support a direct role of mycobacterial infection in inducing IL-10 production by APCs, [37][38][39]62 it is plausible for us to consider the possibility that some level of IL-10 may be actively induced as part of host immune regulatory mechanisms as a means to limit immunopathology, a concession that could be exploited by mycobacteria and has recently been suggested by others. 66 Although our current findings and a large body of literature information support the immune suppressive role of IL-10 in mycobacterial infection, one study shows the addition of exogenous IL-10 to enhance macrophage activation.…”

“…Evidence in the literature suggests that mycobacterial infection can induce the production of IL-10, [37][38][39] which is a critical immune regulatory cytokine. We thus examined whether granuloma cells produced the immune regulatory cytokine IL-10 and compared its level with that by airway luminal cells.…”

IL-10 Plays Opposing Roles during Staphylococcus aureus Systemic and Localized Infections

“…Phagocytosis of Mycobacterium tuberculosis by macrophages results in IL-10 production, which in turn has the capacity to block phagosome maturation in a STAT3-dependent manner, thereby promoting intracellular bacterial survival (9), in addition to inhibiting a Th1 response, thereby facilitating its persistence in the lung (10). Similarly, Bordetella pertussis can promote IL-10 production by both macrophages and dendritic cells (DCs) through expression of the virulence factors filamentous hemagglutinin and adenylate cyclase toxin.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…A separate study found that blockade of IFN-binduced IL-10 signaling partially restored IL1B expression, indicating that type I IFNs may act indirectly to confer their negative effects via IL-10 (83). Because IL-10 has been known to exacerbate murine mycobacterial infections under some circumstances (84), IL-10 induction by type I IFNs could be one mechanism by which type I IFNs impair resistance to mycobacterial infection (85)(86)(87). Interestingly, a recent study suggests that M. tuberculosis-induced type I IFN production can be regulated by IL-1b through PGE 2 (88).…”