Macrophage CD74 contributes to MIF-induced pulmonary inflammation

<p>Abstract</p> <p>Background</p> <p>MIF is a critical mediator of the host defense, and is involved in both acute and chronic responses in the lung. Neutralization of MIF reduces neutrophil accumulation into the lung in animal models. We hypothesized that MIF, in the alveolar space, promotes neutrophil accumulation via activation of the CD74 receptor on macrophages.</p> <p>Methods</p> <p>To determine whether macrophage CD74 surface expression contributes MIF-induced neutrophil accumulation, we instilled recombinant MIF (r-MIF) into the trachea of mice in the presence or absence of anti-CD74 antibody or the MIF specific inhibitor, ISO-1. Using macrophage culture, we examined the downstream pathways of MIF-induced activation that lead to neutrophil accumulation.</p> <p>Results</p> <p>Intratracheal instillation of r-MIF increased the number of neutrophils as well as the concentration of macrophage inflammatory protein 2 (MIP-2) and keratinocyte-derived chemokine (KC) in BAL fluids. CD74 was found to be expressed on the surface of alveolar macrophages, and MIF-induced MIP-2 accumulation was dependent on p44/p42 MAPK in macrophages. Anti-CD74 antibody inhibited MIF-induced p44/p42 MAPK phosphorylation and MIP-2 release by macrophages. Furthermore, we show that anti-CD74 antibody inhibits MIF-induced alveolar accumulation of MIP-2 (control IgG vs. CD74 Ab; 477.1 ± 136.7 vs. 242.2 ± 102.2 pg/ml, p < 0.05), KC (1796.2 ± 436.1 vs. 1138.2 ± 310.2 pg/ml, p < 0.05) and neutrophils (total number of neutrophils, 3.33 ± 0.93 × 10⁴vs. 1.90 ± 0.61 × 10⁴, p < 0.05) in our mouse model.</p> <p>Conclusion</p> <p>MIF-induced neutrophil accumulation in the alveolar space results from interaction with CD74 expressed on the surface of alveolar macrophage cells. This interaction induces p44/p42 MAPK activation and chemokine release. The data suggest that MIF and its receptor, CD74, may be useful targets to reduce neutrophilic lung inflammation, and acute lung injury.</p

Macrophage Migration Inhibitory Factor Antagonist Blocks the Development of Endometriosis In Vivo

Endometriosis, a disease of reproductive age women, is a major cause of infertility, menstrual disorders and pelvic pain. Little is known about its etiopathology, but chronic pelvic inflammation is a common feature in affected women. Beside symptomatic treatment of endometriosis-associated pain, only two main suboptimal therapeutic approaches (hormonal and invasive surgery) are generally recommended to patients and no specific targeted treatment is available. Our studies led to the detection of a marked increase in the expression of macrophage migration inhibitory factor (MIF) in the eutopic endometrium, the peripheral blood and the peritoneal fluid of women with endometriosis, and in early, vascularized and active endometriotic lesions. Herein, we developed a treatment model of endometriosis, where human endometrial tissue was first allowed to implant into the peritoneal cavity of nude mice, to assess in vivo the effect of a specific antagonist of MIF (ISO-1) on the progression of endometriosis and evaluate its efficacy as a potential therapeutic tool. Administration of ISO-1 led to a significant decline of the number, size and in situ dissemination of endometriotic lesions. We further showed that ISO-1 may act by significantly inhibiting cell adhesion, tissue remodeling, angiogenesis and inflammation as well as by altering the balance of pro- and anti-apoptotic factors. Actually, mice treatment with ISO-1 significantly reduced the expression of cell adhesion receptors αv and ß3 integrins (P<0.05), matrix metalloproteinases (MMP) 2 and 9 (P<0.05), vascular endothelial cell growth factor (VEGF) (P<0.01), interleukin 8 (IL8) (P<0.05), cyclooxygenease (COX)2 (P<0.001) and the anti-apoptotic protein Bcl2 (P<0.01), but significantly induced the expression of Bax (P<0.05), a potent pro-apoptotic protein. These data provide evidence that specific inhibition of MIF alters endometriotic tissue growth and progression in vivo and may represent a promising potential therapeutic avenue

Involvement of the Cytokine MIF in the Snail Host Immune Response to the Parasite Schistosoma mansoni

We have identified and characterized a Macrophage Migration Inhibitory Factor (MIF) family member in the Lophotrochozoan invertebrate, Biomphalaria glabrata, the snail intermediate host of the human blood fluke Schistosoma mansoni. In mammals, MIF is a widely expressed pleiotropic cytokine with potent pro-inflammatory properties that controls cell functions such as gene expression, proliferation or apoptosis. Here we show that the MIF protein from B. glabrata (BgMIF) is expressed in circulating immune defense cells (hemocytes) of the snail as well as in the B. glabrata embryonic (Bge) cell line that has hemocyte-like features. Recombinant BgMIF (rBgMIF) induced cell proliferation and inhibited NO-dependent p53-mediated apoptosis in Bge cells. Moreover, knock-down of BgMIF expression in Bge cells interfered with the in vitro encapsulation of S. mansoni sporocysts. Furthermore, the in vivo knock-down of BgMIF prevented the changes in circulating hemocyte populations that occur in response to an infection by S. mansoni miracidia and led to a significant increase in the parasite burden of the snails. These results provide the first functional evidence that a MIF ortholog is involved in an invertebrate immune response towards a parasitic infection and highlight the importance of cytokines in invertebrate-parasite interactions

Maltreatment of children and adolescents with multiple handicaps: Five case examples

Little attention has been directed toward abuse and neglect in children and adolescents with multiple handicaps. This population, however, may be at especially high risk for maltreatment. Factors contributing to added risk include: (a) disruption in mother-infant attachment, (b) greater stress related to care needs and difficult to manage behavior problems, and (c) increased vulnerability due to communication and/or cognitive limitations. Five cases are presented involving abuse and neglect in psychiatrically referred children with multiple handicaps. Cases are discussed in terms of: (a) difficulties in identifying maltreatment in those with multiple handicaps, (b) the need for multidisciplinary intervention with families who engage in maltreatment, and (c) suggestions for future directions that research might take

Abuse and Neglect in Psychiatrically Hospitalized Multihandicapped Children

Medical charts of 150 consecutive admissions of multihandicapped children to a psychiatric hospital were examined to determine the extent and characteristics of abuse and neglect. Results indicated that 39% of the sample experienced or had a history that warranted suspicion of past and/or current maltreatment. Physical abuse was the most frequent type of maltreatment, followed by neglect and sexual abuse. Maltreated multihandicapped patients admitted to the psychiatric unit were less likely to receive diagnoses of organic brain syndrome or profound mental retardation than nonmaltreated multihandicapped counterparts on the same unit. Moreover, data indicated that less severely impaired patients were more likely to be maltreated than were the more severely impaired. Particularly striking was the severity of maltreatment in this multihandicapped sample and the relatively high percentage (40%) of sexually abused patients who were assaulted by multiple perpetrators

Maltreatment in Psychiatrically Hospitalized Children and Adolescents with Developmental Disabilities: Prevalence and Correlates

Objective The goals of this study were (1) to determine the prevalence of child maltreatment in hospitalized children and adolescents with developmental disabilities and concomitant psychiatric disorders, and (2) to identify the contribution of specific mother and child characteristics to the use of more severe disciplinary practices by mothers. Method One hundred thirty-eight psychiatrically hospitalized children and adolescents with developmental disabilities and mothers were assessed using a semistructured interview (Child Abuse and Neglect Interview Schedule) examining factors associated with risk of child maltreatment, and questionnaires measuring maternal and child functioning. The Child Abuse and Neglect Interview Schedule and hospital charts were then used to derive ratings on the prevalence and severity of child maltreatment. Results Findings revealed that 61% of children had experienced some form of severe maltreatment by a care provider in their lifetime. Regression analysis indicated that interactions between high levels of social functioning and disruptive/oppositional behaviors and younger age in children, and low levels of social support and increased anger reactivity in mothers, were most predictive of mothers\u27 use of severe disciplinary practices. Conclusions Maltreatment in psychiatrically hospitalized children and adolescents with disabilities is very prevalent, and it warrants careful clinical assessment. In the psychiatric setting, families in which the child is younger, higher functioning, and behaviorally disruptive, and where mothers have little social support and exhibit increased anger reactivity, are at especially elevated risk