Reprogramming macrophages by plasmin

Resolution of inflammation is a key physiological process regulated at different levels, and failure to achieve resolution may result in chronic inflammation. In this issue of Blood, Sugimoto et al reveal the function of the plasmin system in resolving inflammation by inducing macrophage polarization toward M2 and proresolving phenotypes. Plasmin-derived M2 macrophages produce 2 key effector processes for the resolution of inflammation: annexin A1 and neutrophil efferocytosis.¹ 

The correct management and treatment of chronic inflammation is a challenge in a population that includes increasingly elderly individuals affected by numerous degenerative diseases. Nonresolving inflammation is at the base of different chronic diseases, including cardiovascular disease, type 2 diabetes mellitus, or neurodegenerative diseases.²  Resolution of inflammation is a tightly coordinated and active process necessary for restoring tissue integrity and avoiding excessive damage, fibrosis, and loss of tissue function. Although it is known that resolution of inflammation starts in the first few hours after an inflammatory response begins, we are starting to understand the different mechanisms orchestrating this process.³ 

Macrophages are central innate immune cells that control the inflammatory process. After sensing a noxious stimulus, macrophages polarize to a proinflammatory phenotype that initiates and maintains inflammation by producing different factors, including proinflammatory cytokines, chemokines, and lipids. These proinflammatory macrophages are termed classical or M1.⁴  During the resolving phase of inflammation, macrophages polarize to anti-inflammatory phenotypes characterized by the production of anti-inflammatory cytokines and lipids, increased phagocytosis, and their ability to remodel the damaged tissue; these macrophages are termed alternative or M2.⁴  Because of the high plasticity of macrophages, a plethora of intermediate polarization phenotypes that occur between these 2 extreme phenotypes has been described.^5,6  The modulation of macrophage plasticity toward M2 phenotypes is leading the way discovering novel anti-inflammatory targets by enhancing inflammation resolution.⁶  Although macrophages found in inflammatory-resolving processes are phenotypically distinct to M2,⁷  they resemble and derive from M2-like macrophages.⁸ 

The plasmin system has been widely recognized for its fibrinolytic activity; however, in chronic inflammatory diseases, this system is upregulated, suggesting that plasmin could play a role in maintaining chronic inflammation.⁹  In fact, monocytes treated with plasmin elicit activation of the proinflammatory transcription factor NF-κB. However, plasmin also induces signaling in macrophages via STAT3, a strong M2-related transcription factor.⁹  Sugimoto et al provide evidence indicating that plasmin is able to reprogram macrophages toward M2 and proresolving phenotypes in vivo. For this, the authors injected plasmin into the pleural cavity and found an increase of M2 macrophages; these resolving macrophages could be characterized by a low expression of CD11b. Plasmin also induces an increase of M2-related molecules, including arginase-1, transforming growth factor β, and interleukin-10, with a parallel decrease in the expression of proinflammatory genes. Furthermore, based on a model for resolving inflammation, there is an increase of plasminogen expression and plasmin activity during the resolution phase when compared with the inflammatory phase.

Extending their results to the mechanism of plasmin promoting an anti-inflammatory macrophage phenotype, Sugimoto et al found that the serine protease activity of plasmin is also necessary for increasing neutrophil apoptosis (see figure). Neutrophil apoptosis is a hallmark of inflammation resolution because phagocytosis of apoptotic bodies by macrophages is a potent M2-polarizing signal to generate resolving macrophages.³  Plasmin was also able to increase apoptotic-neutrophil efferocytosis by macrophages, indicating a potentiation of the resolution of the inflammation. Annexin A1 mediated the actions on plasmin-inducing neutrophil apoptosis and efferocytosis (see figure), and in vivo administration of plasmin is able to increase cell surface expression and secretion of annexin A1 by macrophages.¹  Annexin A1 is a potent anti-inflammatory effector molecule of the resolution of inflammation, being one of the main mediators of glucocorticoid anti-inflammatory actions, partially by mediating apoptosis and clearance of apoptotic neutrophils.¹⁰  The work of Sugimoto et al suggests that resolving inflammation through modulation of the plasmin system could represent an advantageous therapy with fewer side effects than the use of glucocorticoids.

This study proposes the plasmin system as an important effector in establishing an efficient resolution of the inflammatory process, paving the way for further studies in the years ahead to test the pharmacological modulation of the plasmin system to achieve an efficient resolution of inflammation. This will ultimately affect the development of novel therapies for a wide range of chronic degenerative diseases with an inflammatory base that affect an increasing elderly population in developed countries.