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Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors.

Clynes R, Maizes JS, Guinamard R, Ono M, Takai T, Ravetch JV - J. Exp. Med. (1999)

Bottom Line: An inhibitory role for FcgammaRII on macrophages is demonstrated by analysis of FcgammaRII-/- macrophages which show greater phagocytic and calcium flux responses upon FcgammaRIII engagement.These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcgammaR expression.Exploiting the FcgammaRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021, USA.

ABSTRACT
Autoantibodies and immune complexes are major pathogenic factors in autoimmune injury, responsible for initiation of the inflammatory cascade and its resulting tissue damage. This activation results from the interaction of immunoglobulin (Ig)G Fc receptors containing an activation motif (ITAM) with immune complexes (ICs) and cytotoxic autoantibodies which initiates and propagates an inflammatory response. In vitro, this pathway can be interrupted by coligation to FcgammaRIIB, an IgG Fc receptor containing an inhibitory motif (ITIM). In this report, we describe the in vivo consequences of FcgammaRII deficiency in the inflammatory response using a mouse model of IC alveolitis. At subthreshold concentrations of ICs that fail to elicit inflammatory responses in wild-type mice, FcgammaRII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from FcgammaRII-/- stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that FcgammaRII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In contrast, complement- and complement receptor-deficient mice develop normal inflammatory responses to suprathreshold levels of ICs, while FcRgamma-/- mice are completely protected from inflammatory injury. An inhibitory role for FcgammaRII on macrophages is demonstrated by analysis of FcgammaRII-/- macrophages which show greater phagocytic and calcium flux responses upon FcgammaRIII engagement. These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcgammaR expression. Exploiting the FcgammaRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.

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Enhanced cytokine and chemokine production in IC-stimulated FcγRII−/− mice. (A) TNF-α production in wild-type (WT) and  FcγRII−/− mice. ELISA measurements of BAL aliquots. (B) Chemotactic  activity of wild-type and FcγRII−/− BAL. Migration of wild-type neutrophils elicited by dilutions of BAL fluids. Chemotactic responses are expressed as the percentage of the total neutrophils loaded into the upper  chamber which migrated into the lower BAL fluid–containing chamber.  Mice received OVA (black bars) or PBS (white bars) intravenously, followed by 30 μg anti-OVA intratracheally. Experimental groups included  four to seven mice per group. Data are presented as mean ± SEM. The P  values for IC-stimulated TNF and chemokine production responses were  0.02 and 0.005, FcγRII−/− vs. wild-type, respectively. Statistical analysis  was performed with an unpaired two-tailed Student's t test.
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Figure 5: Enhanced cytokine and chemokine production in IC-stimulated FcγRII−/− mice. (A) TNF-α production in wild-type (WT) and FcγRII−/− mice. ELISA measurements of BAL aliquots. (B) Chemotactic activity of wild-type and FcγRII−/− BAL. Migration of wild-type neutrophils elicited by dilutions of BAL fluids. Chemotactic responses are expressed as the percentage of the total neutrophils loaded into the upper chamber which migrated into the lower BAL fluid–containing chamber. Mice received OVA (black bars) or PBS (white bars) intravenously, followed by 30 μg anti-OVA intratracheally. Experimental groups included four to seven mice per group. Data are presented as mean ± SEM. The P values for IC-stimulated TNF and chemokine production responses were 0.02 and 0.005, FcγRII−/− vs. wild-type, respectively. Statistical analysis was performed with an unpaired two-tailed Student's t test.

Mentions: The enhanced infiltration of neutrophils seen in IC-stimulated lungs of FcγRII−/− mice suggested that the local production of recruitment factors that include inflammatory cytokines and chemokines might be enhanced in the lungs of FcγRII−/− mice. Indeed, the level of TNF-α production in BAL fluid is enhanced twofold in FcγRII−/− mice (Fig. 5 A). Furthermore, FcγRII−/− BAL fluid contains more than twofold increased neutrophil chemotactic activity compared with control BAL fluid from wild-type stimulated lungs (Fig. 5 B). On the other hand, FcγRII−/−, γ−/−, and wild-type neutrophils show equivalent migratory responses when exposed to chemokine-containing BAL fluid obtained from IC-stimulated wild-type mice (not shown). These data are consistent with the hypothesis that the enhanced neutrophil infiltrative responses seen in FcγRII−/− mice is the result of a lower threshold of IC-triggered activation of FcγR-bearing resident cells, including the alveolar macrophage. This activation of resident cells leads to the increased local production of secondary mediators of inflammation, including TNF-α and chemokines, leading to enhanced recruitment of circulating neutrophils.


Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors.

Clynes R, Maizes JS, Guinamard R, Ono M, Takai T, Ravetch JV - J. Exp. Med. (1999)

Enhanced cytokine and chemokine production in IC-stimulated FcγRII−/− mice. (A) TNF-α production in wild-type (WT) and  FcγRII−/− mice. ELISA measurements of BAL aliquots. (B) Chemotactic  activity of wild-type and FcγRII−/− BAL. Migration of wild-type neutrophils elicited by dilutions of BAL fluids. Chemotactic responses are expressed as the percentage of the total neutrophils loaded into the upper  chamber which migrated into the lower BAL fluid–containing chamber.  Mice received OVA (black bars) or PBS (white bars) intravenously, followed by 30 μg anti-OVA intratracheally. Experimental groups included  four to seven mice per group. Data are presented as mean ± SEM. The P  values for IC-stimulated TNF and chemokine production responses were  0.02 and 0.005, FcγRII−/− vs. wild-type, respectively. Statistical analysis  was performed with an unpaired two-tailed Student's t test.
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Related In: Results  -  Collection

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Figure 5: Enhanced cytokine and chemokine production in IC-stimulated FcγRII−/− mice. (A) TNF-α production in wild-type (WT) and FcγRII−/− mice. ELISA measurements of BAL aliquots. (B) Chemotactic activity of wild-type and FcγRII−/− BAL. Migration of wild-type neutrophils elicited by dilutions of BAL fluids. Chemotactic responses are expressed as the percentage of the total neutrophils loaded into the upper chamber which migrated into the lower BAL fluid–containing chamber. Mice received OVA (black bars) or PBS (white bars) intravenously, followed by 30 μg anti-OVA intratracheally. Experimental groups included four to seven mice per group. Data are presented as mean ± SEM. The P values for IC-stimulated TNF and chemokine production responses were 0.02 and 0.005, FcγRII−/− vs. wild-type, respectively. Statistical analysis was performed with an unpaired two-tailed Student's t test.
Mentions: The enhanced infiltration of neutrophils seen in IC-stimulated lungs of FcγRII−/− mice suggested that the local production of recruitment factors that include inflammatory cytokines and chemokines might be enhanced in the lungs of FcγRII−/− mice. Indeed, the level of TNF-α production in BAL fluid is enhanced twofold in FcγRII−/− mice (Fig. 5 A). Furthermore, FcγRII−/− BAL fluid contains more than twofold increased neutrophil chemotactic activity compared with control BAL fluid from wild-type stimulated lungs (Fig. 5 B). On the other hand, FcγRII−/−, γ−/−, and wild-type neutrophils show equivalent migratory responses when exposed to chemokine-containing BAL fluid obtained from IC-stimulated wild-type mice (not shown). These data are consistent with the hypothesis that the enhanced neutrophil infiltrative responses seen in FcγRII−/− mice is the result of a lower threshold of IC-triggered activation of FcγR-bearing resident cells, including the alveolar macrophage. This activation of resident cells leads to the increased local production of secondary mediators of inflammation, including TNF-α and chemokines, leading to enhanced recruitment of circulating neutrophils.

Bottom Line: An inhibitory role for FcgammaRII on macrophages is demonstrated by analysis of FcgammaRII-/- macrophages which show greater phagocytic and calcium flux responses upon FcgammaRIII engagement.These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcgammaR expression.Exploiting the FcgammaRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021, USA.

ABSTRACT
Autoantibodies and immune complexes are major pathogenic factors in autoimmune injury, responsible for initiation of the inflammatory cascade and its resulting tissue damage. This activation results from the interaction of immunoglobulin (Ig)G Fc receptors containing an activation motif (ITAM) with immune complexes (ICs) and cytotoxic autoantibodies which initiates and propagates an inflammatory response. In vitro, this pathway can be interrupted by coligation to FcgammaRIIB, an IgG Fc receptor containing an inhibitory motif (ITIM). In this report, we describe the in vivo consequences of FcgammaRII deficiency in the inflammatory response using a mouse model of IC alveolitis. At subthreshold concentrations of ICs that fail to elicit inflammatory responses in wild-type mice, FcgammaRII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from FcgammaRII-/- stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that FcgammaRII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In contrast, complement- and complement receptor-deficient mice develop normal inflammatory responses to suprathreshold levels of ICs, while FcRgamma-/- mice are completely protected from inflammatory injury. An inhibitory role for FcgammaRII on macrophages is demonstrated by analysis of FcgammaRII-/- macrophages which show greater phagocytic and calcium flux responses upon FcgammaRIII engagement. These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcgammaR expression. Exploiting the FcgammaRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.

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Related in: MedlinePlus