Macrophage Polarization in Leprosy-HIV Co-infected Patients

Abstract

In HIV-infected individuals, a paradoxical clinical deterioration may occur in preexisting leprosy when highly active antiretroviral therapy (HAART)-associated reversal reaction (RR) develops. Leprosy-HIV co-infected patients during HAART may present a more severe form of the disease (RR/HIV), but the immune mechanisms related to the pathogenesis of leprosy-HIV co-infection remain unknown. Although the adaptive immune responses have been extensively studied in leprosy-HIV co-infected individuals, recent studies have described that innate immune cells may drive the overall immune responses to mycobacterial antigens. Monocytes are critical to the innate immune system and play an important role in several inflammatory conditions associated with chronic infections. In leprosy, different tissue macrophage phenotypes have been associated with the different clinical forms of the disease, but it is not clear how HIV infection modulates the phenotype of innate immune cells (monocytes or macrophages) during leprosy. In the present study, we investigated the phenotype of monocytes and macrophages in leprosy-HIV co-infected individuals, with or without RR. We did not observe differences between the monocyte profiles in the studied groups; however, analysis of gene expression within the skin lesion cells revealed that the RR/HIV group presents a higher expression of macrophage scavenger receptor 1 (MRS1), CD209 molecule (CD209), vascular endothelial growth factor (VEGF), arginase 2 (ARG2), and peroxisome proliferator-activated receptor gamma (PPARG) when compared with the RR group. Our data suggest that different phenotypes of tissue macrophages found in the skin from RR and RR/HIV patients could differentially contribute to the progression of leprosy.

Keywords: HIV-1; co-infection; leprosy; macrophage phenotype; monocyte subsets.

Figure 1

Profile Monocytes in reversal reaction (RR) patients with and without HIV. (A) Dot plot representing the gate strategy used for analysis. (B) The percentages of HLA-DR⁺CD14⁺CD16⁻ and (C) HLA-DR⁺CD14⁺CD16⁺ monocytes were demonstrated. Healthy controls (HC; n = 5), RR (n = 5), RR/HIV (n = 8).

Figure 2

The gene profile of skin macrophages. Real-time PCR was performed in order to evaluate the macrophage phenotype in the skin from paucibacillary leprosy (BT; n = 6), reversal reaction (RR; n = 5), BT/HIV (n = 4), and RR/HIV (n = 8) patients. Data are presented as mean ± SD, *p ≤ 0.05; **p ≤ 0.01.

Figure 3

Association networks between pro- and anti-inflammatory macrophage genes in skin cells of leprosy patients with or without HIV. Association networks in paucibacillary leprosy (BT), reversal reaction (RR), BT/HIV, and RR/HIV patients. The intensity of the line represents the degree of association between the macrophage genes. Mean association is represented by slim lines, and a strong association is represented by a strong line.

Figure 4

Pro- and anti-inflammatory markers in skin cells from leprosy patients co-infected or not with HIV. Skin lesion biopsies were obtained from leprosy patients, co-infected or not, as indicated. Immunohistochemical (IHC) analysis of CD163 (CD163), PPAR-γ (PPARG), arginase 2 (ARG2), SRA-1 (MRS1), HO-1 (HMOX1), IDO1 (IDO), and CXCL-10 (CXCL10) was demonstrated. Representative micrographs from paucibacillary leprosy (BT; n = 6), reversal reaction (RR; n = 5), BT/HIV (n = 4), and RR/HIV (n = 8) patients are shown. Scale bar: 100 μm.