Gelatinases A and B (
matrix metalloproteinase 2 [
MMP-2] and
MMP-9, respectively) can induce basal membrane breakdown and leukocyte migration, but their role in
leprosy skin
inflammation remains unclear. In this study, we analyzed clinical specimens from
leprosy patients taken from stable, untreated skin lesions and during reactional episodes (reversal reaction [RR] and
erythema nodosum leprosum [ENL]). The participation of
MMPs in disease was suggested by (i) increased
MMP mRNA expression levels in skin biopsy specimens correlating with the expression of
gamma interferon (IFN-gamma) and
tumor necrosis factor alpha (
TNF-alpha), (ii) the detection of the
MMP protein and enzymatic activity within the inflammatory infiltrate, (iii) increased
MMP levels in patient sera, and (iv) the in vitro induction of MMP-9 by Mycobacterium leprae and/or
TNF-alpha. It was observed that IFN-gamma,
TNF-alpha, MMP-2, and MMP-9
mRNA levels were higher in tuberculoid than lepromatous lesions. In contrast,
interleukin-10 and tissue inhibitor of
MMP (TIMP-1) message were not differentially modulated. These data correlated with the detection of the
MMP protein evidenced by immunohistochemistry and confocal microscopy. When RR and ENL lesions were analyzed, an increase in
TNF-alpha, MMP-2, and MMP-9, but not
TIMP-1,
mRNA levels was observed together with stronger
MMP activity (zymography/in situ zymography). Moreover, following in vitro stimulation of peripheral blood cells, M. leprae induced the expression of MMP-9 (
mRNA and
protein) in cultured cells. Overall, the present data demonstrate an enhanced
MMP/TIMP-1 ratio in the inflammatory states of
leprosy and point to potential mechanisms for tissue damage. These results pave the way toward the application of new therapeutic interventions for
leprosy reactions.