Autophagy Impairment Is Associated With Increased Inflammasome Activation and Reversal Reaction Development in Multibacillary Leprosy

Abstract

Leprosy reactions are responsible for incapacities in leprosy and represent the major cause of permanent neuropathy. The identification of biomarkers able to identify patients more prone to develop reaction could contribute to adequate clinical management and the prevention of disability. Reversal reaction may occur in unstable borderline patients and also in lepromatous patients. To identify biomarker signature profiles related with the reversal reaction onset, multibacillary patients were recruited and classified accordingly the occurrence or not of reversal reaction during or after multidrugtherapy. Analysis of skin lesion cells at diagnosis of multibacillary leprosy demonstrated that in the group that developed reaction (T1R) in the future there was a downregulation of autophagy associated with the overexpression of TLR2 and MLST8. The autophagy impairment in T1R group was associated with increased expression of NLRP3, caspase-1 (p10) and IL-1β production. In addition, analysis of IL-1β production in serum from multibacillary patients demonstrated that patients who developed reversal reaction have significantly increased concentrations of IL-1β at diagnosis, suggesting that the pattern of innate immune responses could predict the reactional episode outcome. In vitro analysis demonstrated that the blockade of autophagy with 3-methyladenine (3-MA) in Mycobacterium leprae-stimulated human primary monocytes increased the assembly of NLRP3 specks assembly, and it was associated with an increase of IL-1β and IL-6 production. Together, our data suggest an important role for autophagy in multibacillary leprosy patients to avoid exacerbated inflammasome activation and the onset of reversal reaction.

Enhanced inflammasome activation and reduced sphingosine-1 phosphate S1P signalling in a respiratory mucoobstructive disease model

“…Increased bright specks of NLRP3 and IL-1β detected in the lung of βENaC overexpressing mice were highly localized to the vicinity of mucus plaques and plugs. Specks vs. homogenous fluorescence reflects oligomeric vs. monomeric states and is a method for the detection of NLRP3 inflammasome activation [21]. In the lungs, measurement of IL-1β/ IL-18 in BAL is a commonly accepted technique to detect inflammasome activation, particularly in mouse studies [22].…”

Advances in the Immunology and Genetics of Leprosy

“…Even more, autophagy was also suggested to play an important role in T1R in multibacillary leprosy. In a study of multibacillary leprosy (BL and LL), the researchers found that autophagy was downregulated in patients who developed T1R in the future compared to patients who did not develop T1R (20). And the authors also demonstrated a significantly higher level of IL-1β in the serum of T1R group months before T1R onset, suggesting IL-1β as a potential marker for T1R prediction (20).…”

Macrophage Polarization in Leprosy–HIV Co-infected Patients

“…As observed in Figures 1B,C Previous work from our group has demonstrated the presence of different tissue macrophage phenotypes in skin from paucibacillary and multibacillary leprosy patients. Whereas, proinflammatory markers were more expressed in paucibacillary, anti-inflammatory and scavenger receptor expressions were higher in samples from the multibacillary patients (6). In order to investigate the cell phenotypes present in lesions from leprosy-HIV co-infected patients, with or without RR, we evaluated pro-, and anti-inflammatory macrophage markers (pro-inflammatory: IL12B, IL23A, IL1B, CXCL10; and anti-inflammatory: VEGF, ARG2, PPARG, PDGFA, CD163, MRS1) as well as markers that could be present in both macrophage phenotypes, depending on the environment (IDO, HMOX1, CD209).…”

“…In contrast, skin cells from multibacillary patients are highly phagocytic and have a suppressive phenotype marked by an increase of alternatively activated macrophage markers, CD163 and macrophage scavenger receptor 1 (MRS1) (3,5). The macrophage phenotype that predominates in multibacillary patients contributes to bacterial survival and persistence inside cells by an IL-10-mediated pathway (2,6).…”