Abstract
Leprosy is a persistent infectious disease caused by Mycobacterium leprae that still affects over 200,000 new patients annually. The host genetic background is an important risk factor for leprosy susceptibility and the PARK2 gene is a replicated leprosy susceptibility candidate gene. The protein product of PARK2, Parkin, is an E3 ubiquitin ligase that is involved in the development of various forms of Parkinsonism. The human macrophage is both a natural host cell of M. leprae as well as a primary mediator of natural immune defenses, in part by secreting important pro-inflammatory cytokines and chemokines. Here, we report that down-regulation of Parkin in THP-1 macrophages, human monocyte-derived macrophages and human Schwann cells resulted in a consistent and specific decrease in interleukin-6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1/CCL2) production in response to mycobacteria or LPS. Interestingly, production of IL-6 at 6 hours by THP-1 cells stimulated with live M. leprae and M. bovis BCG was dependent on pretreatment with 1,25-dihydroxyvitamin D3 (VD). Parkin knockdown in VD-treated cells blocked IL-6 induction by mycobacteria. However, IκB-α phosphorylation and levels of IκB-ξ, a nuclear protein required for IL-6 expression, were not affected by Parkin silencing. Phosphorylation of MAPK ERK1/2 and p38 was unaffected by Parkin silencing while JNK activation was promoted but did not explain the altered cytokine production. In a final set of experiments we found that genetic risk factors of leprosy located in the PARK2 promoter region were significantly correlated with M. leprae sonicate triggered CCL2 and IL6 transcript levels in whole blood assays. These results associated genetically controlled changes in the production of MCP-1/CCL2 and IL-6 with known leprosy susceptibility factors.
Highlights
Leprosy, called Hansen’s disease, is a persistent infectious disease caused by Mycobacterium leprae
To better understand a possible contribution of PARK2 to host effector mechanisms in leprosy patients, we developed a cellular model to test the contribution of the PARK2 encoded parkin protein to host responses to mycobacterial antigens
We observed that parkin was a mediator of IL-6 production in response to mycobacterial antigen in both THP-1 macrophages and human Schwann cells while human monocyte-derived macrophages needed to be preactivated with VitD to show the same impact
Summary
Called Hansen’s disease, is a persistent infectious disease caused by Mycobacterium leprae. While leprosy can be transmitted by armadillos in the Southern United States [1] humans are the most important reservoir for M. leprae and the more common route is human-human transmission. Leprosy can lead to the destruction of peripheral nerves and subsequent extreme deformities of the skin and peripheral limbs. Despite effective chemotherapy and active case finding, the global number of new leprosy cases is estimated at over 200,000 annually [2]. Microbiologically cured patients require follow-up to prevent nerve damage from sequellae of the disease. Due to the extreme social stigma and the long term follow-up, leprosy presents a large emotional and financial burden for affected communities and health care systems
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