An Important Role of Prostanoid Receptor EP2 in Host Resistance to Mycobacterium tuberculosis Infection in Mice

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis, resides and replicates within susceptible hosts by inhibiting host antimicrobial mechanisms. Prostaglandin E(2) (PGE(2)), produced by M. tuberculosis-infected macrophages, exerts a variety of immunomodulatory functions via 4 receptors (EP1-EP4), each mediating distinct PGE(2) functions. Here, we show that M. tuberculosis infection selectively upregulates EP2 messenger RNA expression in CD4(+) T cells. We found that EP2 deficiency in mice increases susceptibility to M. tuberculosis infection, which correlated with reduced antigen-specific T-cell responses and increased levels of CD4(+)CD25(+)Foxp3(+) T-regulatory cells. These findings have revealed an important role for EP2 in host immune defense against tuberculosis. As a G protein-coupled receptor, EP2 could serve as a target for immunotherapy of tuberculosis.

Eicosanoids, Prostaglandins, and the Progression of Tuberculosis

“…Splenocytes from these EP2 −/− mice, however, proliferated at a higher rate in response to M. tuberculosis-specific antigens relative to splenocytes from parental BL/6 mice [10]. Furthermore, spleen cells from EP2 −/− mice expressed higher levels of iTreg and Th17, but not Th2 cytokines in an antigenspecific manner.…”

“…The results of Kaul et al clearly demonstrate an important role for EP2-mediated PGE2 signaling in the control of M. tuberculosis infections [10]. This observation is not an isolated one.…”

“…A confirmation of these observations was provided by flow cytometry and immunohistochemistry-based enumeration of total cell populations during different experiments. Twice as many CD4 + CD25 + FoxP3 + (iTreg phenotype) cells, and significantly more Th17 (IL-17 + ) cells were present in the lungs of EP2 −/− relative to BL/6 mice when assessed by flow cytometry [10]. Similarly, significantly more iTregs were detected in the granulomatous lesions of EP2 −/− mice than in BL/6 mice when analyzed by immunohistochemistry.…”

“…Kaul et al convincingly show that M. tuberculosis infection specifically regulates EP2 expression in DCs. Using a knock-out mouse model, these authors surprisingly demonstrate that BL/6:EP2 −/− mice are significantly more susceptible to aerosol infection with M. tuberculosis relative to congenic BL/6 mice [10]. Four weeks postinfection, about 4-fold more bacilli were present in the lungs, as well as spleens, of EP2 −/− rather than BL/6 mice.…”

“…PGE2-mediated inhibition of AICD occurs via EP2. In this issue of the Journal of Infectious Diseases, Kaul et al [10] studied the expression of all four PGE2 receptors during the progression of tuberculosis in a BL/6 mouse model and report that M. tuberculosis infection induces the expression of EP2 in spleen-derived CD4 + T cells, especially during the late stages of infection.…”