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Evaluation of the participation of M1 and M2 macrophages in the immune response against the dimorphic fungus Paracoccidioides brasiliensis

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Munir Regini Paião
Total Authors: 1
Document type: Doctoral Thesis
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
Defense date:
Examining board members:
Ronei Luciano Mamoni; Sandro Rogerio de Almeida; Angela Maria Victoriano de Campos Soares; Wirla Maria da Silva Cunha Tamashiro; Nicola Amanda Conran Zorzetto
Advisor: Ronei Luciano Mamoni; Maria Heloisa de Souza Lima Blotta

Background: Paracoccidioidomycosis (PCM) is a systemic mycosis with the highest incidence in Latin America. It is caused by thermal dimorphic fungus from Paracoccidioides genus (P. brasiliensis e P. lutzii). Among the cells of the innate immune system, macrophages play a preponderant role in the recognition and removal of pathogens and in the determination of the adaptive immune response in several diseases, including PCM. It is known that these cells can acquire distinct phenotypes, depending on their differentiation microenvironment, presenting diverse effector functions being classified as: M1 (pro-inflammatory) or M2 (anti-inflammatory). Objective: The aims of this study were: to evaluate the phenotypic and functional characteristics of M1 and M2 macrophages when stimulated in vitro with P. brasiliensis yeast cells, including their role in the activation and differentiation of T lymphocytes; and the characterization of these macrophages in oral-mucosa and lymph node biopsies from PCM patients. Methods: Monocytes from peripheral blood of healthy donors were purified and differentiated in M1 or M2 macrophages by the treatment with GM-CSF or M-CSF, respectively, for 5 days. After differentiation the two types of macrophages were stimulated with P. brasiliensis yeast cells (Pb18 strain) and evaluated in relation to the following phenotypic and functional characteristics: surface markers expression, granuloma formation capacity, fungicidal and phagocytic activity, production of arginase-1, H2O2 and NO and production of cytokines, chemokines and matrix metalloproteinases (MMPs), Furthermore, we co-cultured M1 or M2 macrophages stimulated by Pb18 yeast cells with autologous purified T lymphocytes. The characterization of macrophages in biopsies from patients was perfomed by de immune histochemical technique. Results: We found that M1 cells, when challenged with Pb18 yeast cells, presented higher productions of IL12p70, IL-6, TNF-?, MMP-1, MMP-9, H2O2 and NO; higher expression of CD1a, CD80, CD86, MHC II and dectin-1; a higher capacity to form granuloma when compared with M2 cells. On the other hand, M2 cells presented higher productions of IL10, IL1-? and arginase-1; an elevated expression of CD209, CD205, CD206, CD163, CD36, CD14, CD16, TLR2 and TLR4, besides a higher fungicidal and phagocytic capability. Moreover, we found that both M1 and M2 macrophages induced the activation of T lymphocytes which presented opposing profiles. Whereas M1 macrophages induced the differentiation of Th1 and Th17 lymphocytes, M2 macrophages stimulated the differentiation of Th2 e Treg lymphocytes. We also observed in the lesions of acute form patients (lymph nodes), the predominance of macrophages presenting M2 characteristics (high expression of CD206 and IL-10 production). Conclusion: Our results show that both M1 and M2 macrophages can develop opposing, but complementary roles in the initial immune response against the P. brasiliensis infection, as well as in the activation and differentiation of T lymphocytes. M1 macrophages can be important to the inicial inflammatory response and restrainment of fungal dissemination, though can contribute to an exacerbated inflammatory response and tissue damage. M2 macrophages, on the other hand, can be important to the control of the inflammatory response, but contribute to the dissemination of the fungus (AU)

FAPESP's process: 12/14828-8 - Evaluation of the involvement of M1 and M2 macrophages in the response to the dimorphic fungus Paracoccidioides brasiliensis
Grantee:Munir Regini Paião
Support Opportunities: Scholarships in Brazil - Doctorate