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Published on: April 29, 2015
Endogenous interferon production by endotoxin-responsive macrophages provides an autostimulatory differentiation
Abstract:
Previous studies have demonstrated that peritoneal macrophages (resident or thioglycolate-induced) derived from mouse strains fully responsive to gram-negative endotoxins continue to differentiate in vitro, as evidenced by an increased capacity to phagocytose via the Fc receptor with time in culture. In contrast, macrophages derived from endotoxin-hyporesponsive mouse strains (e.g., C3H/HeJ or C57BL/10ScN) exhibit no such increase in phagocytic capacity, and, in fact, significantly lose the capacity to phagocytose particles opsonized with immunoglobulin G with time in culture. This defect was found to be fully correctable by the addition to the cultures of an exogenous source of alpha, beta, or gamma interferon. In this study, we compared C3H/HeN (endotoxin-responsive) and C3H/HeJ (endotoxin-responsive) and C3H/HeJ (endotoxin-hyporesponsive) macrophages in an attempt to elucidate the mechanism responsible for this difference in phagocytic (differentiative) potential. The following observations support the hypothesis that endotoxin-responsive macrophages, in contrast to endotoxin-hyporesponsive macrophages, produce significantly higher levels of an autostimulatory differentiation signal that appears to be macrophage-derived interferon. (i) Anti-alpha/beta-interferon antibody greatly reduces the ability of C3H/HeN macrophages to phagocytose opsonized erythrocytes: (ii) C3H/HeJ macrophages can be made more phagocytic by coculture with C3H/HeN macrophages or by treatment with supernatants derived from C3H/HeN macrophage cultures; and (iii) C3H/HeN macrophages spontaneously lose Mac-1 antigen with time in culture. C3H/HeJ macrophages must be interferon-treated to be equivalently down-regulated.
Insights
Endotoxin-responsive macrophages enhance phagocytosis through self-produced interferon, unlike hyporesponsive ones. This difference in macrophage differentiation is corrected by adding external interferon.
Area of Science:
- Immunology
- Cell Biology
Background:
- Macrophages from endotoxin-responsive mice show increased phagocytosis in vitro, while hyporesponsive macrophages lose this capacity.
- This phagocytic defect in hyporesponsive macrophages can be reversed by adding exogenous interferon (alpha, beta, or gamma).
Purpose of the Study:
- To investigate the mechanism behind the differing phagocytic potential between endotoxin-responsive (C3H/HeN) and endotoxin-hyporesponsive (C3H/HeJ) mouse macrophages.
- To test the hypothesis that endotoxin-responsive macrophages produce higher levels of an autostimulatory, macrophage-derived interferon signal.
Main Methods:
- Comparison of peritoneal macrophages from C3H/HeN and C3H/HeJ mouse strains.
- In vitro culture experiments assessing phagocytic capacity (opsonized erythrocyte uptake).
- Treatment with anti-interferon antibodies, co-culture with other macrophages, and use of macrophage-derived supernatants.
Main Results:
- Anti-interferon antibodies significantly reduced phagocytosis in C3H/HeN macrophages.
- C3H/HeJ macrophages' phagocytic ability improved when co-cultured with C3H/HeN macrophages or treated with their supernatants.
- C3H/HeN macrophages showed spontaneous loss of Mac-1 antigen, which required interferon treatment in C3H/HeJ macrophages for equivalent down-regulation.
Conclusions:
- Endotoxin-responsive macrophages produce a crucial autostimulatory interferon signal that promotes differentiation and phagocytosis.
- This endogenous interferon production is deficient in endotoxin-hyporesponsive macrophages, explaining their impaired phagocytic capacity.
- Interferon plays a key role in regulating macrophage differentiation and Fc receptor-mediated phagocytosis.
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