Inflammasome Signaling in Pure Neural Leprosy: Evidence for a Peripheral Nerve Microenvironment-Dependent Inflammatory Response

Victor Hugo Pires de Azeredo, Mariana Martins de Athaide, Beatriz Junqueira de Souza, Márcia Maria Jardim Rodrigues, Tatiana Pereira da Silva, Roberta Olmo Pinheiro

Leprosy, caused by Mycobacterium leprae, is a chronic infectious disease in which peripheral nerve damage is the major cause of irreversible disability. Although M. leprae directly infects Schwann cells (SCs), the inflammatory mechanisms driving neural injury remain poorly understood. Given the role of inflammasomes in neuroinflammation, we investigated their contribution to nerve damage in pure neural leprosy (PNL). Patients evaluated at the Souza Araújo Outpatient Clinic were assessed for molecular and systemic markers of inflammasome activation. Complementary experiments were performed using ST88-14 human SCs exposed for 24 h to viable or irradiated M. leprae. Peripheral nerve samples from PNL patients exhibited an inflammasome-associated transcriptional signature, with significantly increased AIM2 and IL18 expression, while circulating IL-1β levels were also significantly elevated. In contrast, direct exposure of isolated SCs to M. leprae failed to reproduce this response. Expression of NLRP1, NLRP3, IL1B, IL18, and CASP1 were not significantly altered, and NLRP1 and pro-caspase-1 protein levels remained unchanged. Moreover, M. leprae neither increased IL-1β release nor affected SC viability. These findings reveal a dissociation between inflammasome-associated inflammation in PNL patients and the response of isolated M. leprae-infected SCs, suggesting that inflammasome activation is not primarily Schwann-cell autonomous but depends on the immune microenvironment of the infected peripheral nerve. Thus, neuroimmune crosstalk may represent a key driver of inflammation-mediated nerve injury and a potential target for preventing neurological damage in leprosy.

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