Differential Macrophage Polarization from Pneumocystis in Immunocompetent and Immunosuppressed Hosts: Potential Adjunctive Therapy during Pneumonia

Abstract

We explored differential polarization of macrophages during infection using a rat model of Pneumocystis pneumonia. We observed enhanced pulmonary M1 macrophage polarization in immunosuppressed (IS) hosts, but an M2 predominant response in immunocompetent (IC) hosts following Pneumocystis carinii challenge. Increased inflammation and inducible nitric oxide synthase (iNOS) levels characterized the M1 response. However, macrophage ability to produce nitric oxide was defective. In contrast, the lungs of IC animals revealed a prominent M2 gene signature, and these macrophages effectively elicited an oxidative burst associated with clearance of Pneumocystis. In addition, during P. carinii infection the expression of Dectin-1, a critical receptor for recognition and clearance of P. carinii, was upregulated in macrophages of IC animals but suppressed in IS animals. In the absence of an appropriate cytokine milieu for M2 differentiation, Pneumocystis induced an M1 response both in vitro and in vivo. The M1 response induced by P. carinii was plastic in nature and reversible with appropriate cytokine stimuli. Finally, we tested whether macrophage polarization can be modulated in vivo and used to help manage the pathogenesis of Pneumocystis pneumonia by adoptive transfer. Treatment with both M1 and M2 cells significantly improved survival of P. carinii-infected IS hosts. However, M2 treatment provided the best outcomes with efficient clearance of P. carinii and reduced inflammation.

Helper T‐cell responses and pulmonary fungal infections

“…Other studies have implicated Type 1 and Type 2 immunity in protecting against Pneumocystis infection. Some studies have correlated robust Type 2 responses and M2‐polarized macrophage responses with protection against Pneumocystis and fungal killing . Conversely, artificial induction of IFN‐ γ responses during Pneumocystis infection in the absence of CD4 T‐cell help restores control of infection, suggesting that Type 1 responses at least have the potential to mediate protection against Pneumocystis .…”

New advances in understanding the host immune response to Pneumocystis

“…In contrast, rats with a competent immune response had a more prominent alternative macrophage (M2) response and cleared infection. Treatment of immunosuppressed rats with M2 cells reverted rats to a protected phenotype [33, 34]. …”

“…Th2 responses to Pneumocystis drive an allergic reaction in healthy hosts. APCs = antigen presenting cells, Th = T helper, M1 = classically activated macrophages, M2 = alternatively activated macrophages [9, 10, 32, 34, 39]. …”

Intrinsic Programming of Alveolar Macrophages for Protective Antifungal Innate Immunity Against Pneumocystis Infection

“…Alternatively activated M2 macrophages are associated with Pc clearance ( 13 ) and possess anti-Pc effector function ( 14 ), which may represent a critical mechanism by which CD4 + T cells modulate macrophage function for effective host defense. A recent study found that AMs from Pc-susceptible immunosuppressed hosts adopt a classically activated M1 phenotype, while those from immunocompetent hosts adopt an M2 phenotype following Pc infection ( 15 ). These investigators also determined that the adoptive transfer of either M1 or M2 macrophages to Pc-infected immunosuppressed hosts enhanced Pc clearance, but less inflammation and better outcomes were observed following M2 transfer.…”