Abnormalities in chemokine levels in schizophrenia and their clinical correlates
Introduction
Persons with schizophrenia have increased morbidity and mortality rates from medical illnesses, especially cardiovascular diseases (Brown, 1997, Inskip et al., 1998). Schizophrenia has been associated with immune dysfunction and inflammation (Dickerson et al., 2016), which may contribute to accelerated aging and greater comorbidity and mortality (Kirkpatrick et al., 2008). The large CATIE study reported higher levels of inflammatory markers (Meyer et al., 2009) and elevated coronary heart disease risk in people with schizophrenia, especially among women (Goff et al., 2005). Autoimmune diseases and chronic inflammatory conditions occur with higher frequency in persons with schizophrenia (Benros et al., 2014b). Individuals with schizophrenia reportedly have increased plasma concentrations of C-reactive protein, interleukin (IL)-6, IL-6 receptor, tumor necrosis factor-α, and soluble IL-2 receptor (Joseph et al., 2015, Lin et al., 1998, Maes et al., 1995, Mondelli et al., 2015, Naudin et al., 1996). Also, treatment with non-steroidal anti-inflammatory cyclooxygenase-2 inhibitors was shown to reduce psychotic symptoms in patients with recent-onset psychosis but not chronic psychosis (Nitta et al., 2013, Rapaport et al., 2005). Taken together, immune activation/inflammation is associated with schizophrenia, but more comprehensive investigations are necessary to specify the nature of immune alterations and their clinical correlates.
Chemokines constitute a family of small (7–12 kDA) cytokines and induce directed chemotaxis in nearby responsive cells. Chemokines play an integral role in immune function, mediating leukocyte migration and trafficking, and inflammatory responses (Foxman et al., 1997, Murphy et al., 2000b, Springer, 1994). Recent studies suggest direct roles of chemokines in the central nervous system (CNS), including neuroendocrine function, neurotransmission, and neurodegeneration (Reaux-Le Goazigo et al., 2013). Elevated levels of chemokines in the CNS and blood are observed in several neuroinflammatory disorders such as multiple sclerosis (Balashov et al., 1999, Sorensen et al., 1999), as well as psychiatric conditions including depression, bipolar disorder, and schizophrenia (Eyre et al., 2016, Panizzutti et al., 2015, Stuart and Baune, 2014).
The literature on chemokine levels in schizophrenia is informative but has limitations. Most studies examined a relatively small number of chemokines in male-dominant samples. These investigations vary widely in considering potential demographic and clinical correlates in analyzing schizophrenia-chemokine relationships (Beumer et al., 2012, Xu et al., 2015). Monocyte chemoattractant protein (MCP)-1 is the best-studied chemokine, but the findings are equivocal with nearly equal numbers of studies showing significantly higher (Beumer et al., 2012, Dimitrov et al., 2013, Domenici et al., 2010, Reale et al., 2011, Zakharyan et al., 2012) or similar (Asevedo et al., 2013, Brambilla et al., 2014, Di Nicola et al., 2013, Martinez-Cengotitabengoa et al., 2012, Schwarz et al., 2012, Teixeira et al., 2008) levels between schizophrenia patients and healthy comparison subjects (HCs). There are also inconsistent findings for IL-8 (Dennison et al., 2012, Di Nicola et al., 2013, Erbagci et al., 2001, Kaminska et al., 2001, Maes et al., 2002, O'Brien et al., 2008, Ramsey et al., 2013, Reale et al., 2011, Zhang et al., 2002), Eotaxin-1 (Asevedo et al., 2013, Domenici et al., 2010, Pedrini et al., 2014, Ramsey et al., 2013, Teixeira et al., 2008), and macrophage derived chemokine (MDC; Brambilla et al., 2014, Dimitrov et al., 2013, Domenici et al., 2010, Ramsey et al., 2013, Schwarz et al., 2012). Other chemokines, including macrophage inflammatory protein (MIP)-1α (Asevedo et al., 2013, Brambilla et al., 2014, Dimitrov et al., 2013, Domenici et al., 2010, Nikkila et al., 2002, Schwarz et al., 2012, Teixeira et al., 2008, Zakharyan et al., 2012), MIP-1β (Beumer et al., 2012, Brambilla et al., 2014, Dimitrov et al., 2013, Domenici et al., 2010, Schwarz et al., 2012), and interferon-induced protein-10 (IP-10; Asevedo et al., 2013, Brambilla et al., 2014, Dimitrov et al., 2013, Teixeira et al., 2008) have not been shown to differ between people with schizophrenia and HCs. Finally, MCP-4 (Teixeira et al., 2008), Eotaxin-3 (Schwarz et al., 2012), fractalkine (Dimitrov et al., 2013), and thymus and activation-regulated chemokine (TARC) have received little attention in schizophrenia. Men with schizophrenia have shown higher chemokine levels (e.g., IL-8, MCP-1, MDC, MIP-1α, and MIP-1β) than women with schizophrenia in some studies (Beumer et al., 2012, Domenici et al., 2010, Ramsey et al., 2013).
We assessed plasma levels of 11 chemokines in a well-characterized group of outpatients with schizophrenia and HCs. These chemokines included eight CC motif chemokine ligands: MCP-1 (CCL2), MIP-1α (CCL3), MIP-1β (CCL4), Eotaxin-1 (CCL11), MCP-4 (CCL13), TARC (CCL17), MDC (CCL22), Eotaxin-3 (CCL26); two CXC motif ligands: IL-8 (CXCL8) and IP-10 (CXCL10); and one CX3C motif ligand: fractalkine (CX3CL1). Our panel contained chemokines of both innate and adaptive immunity with inflammatory (MCP-1, MIP-1α, MIP-1β, MCP-4, Eotaxin-3, IL-8, IP-10), and dual (both inflammatory and homeostatic; Eotaxin-1, TARC, MDC, and fractalkine) functions (Zlotnik and Yoshie, 2012), and also includes chemokines with known roles in the CNS (MCP-1, MIP-1α, MIP-1β, Eotaxin-1, IL-8, IP-10, and fractalkine) (Stuart et al., 2015). We compared levels of each chemokine in our panel between people with schizophrenia and HCs. For those plasma chemokines that differed between the two groups, we examined whether the differences remained significant after adjusting for covariates. We also examined subgroups of patients who were more comparable to the HCs on body mass index (BMI) and smoking. The relationship of age and gender to the chemokines was examined separately in the persons with schizophrenia and HCs. Finally, we created a Chemokine Index (CI) based on a combination of markers that differed most between the two diagnostic groups, and explored clinical correlates of the Index in the two groups.
Section snippets
Participants
The protocol was approved by the University of California, San Diego (UCSD) Human Research Protections Program. Participants provided written informed consent. These included 134 outpatients with schizophrenia or schizoaffective disorder (hereafter referred to collectively as schizophrenia) and 112 HCs with no history of major neuropsychiatric disorder, recruited from the greater San Diego community and enrolled in an ongoing study of aging in schizophrenia. Schizophrenia diagnosis was
Results
There was, as expected, no significant difference in age or gender between the people with schizophrenia and HCs (Table 1). The people with schizophrenia had a slightly lower proportion of Caucasians, lower education level, greater cigarette smoking, higher BMI, greater medical comorbidity and disease risk, more severe depressive symptoms, and poorer executive functioning than HCs. Persons with schizophrenia were more likely to be taking psychotropic medications and anti-inflammatory agents.
Discussion
Plasma levels of five CC chemokines were greater in schizophrenia compared to HC: MCP-1/CCL2, MIP-1β/CCL4, Eotaxin-1/CCL11, TARC/CCL17, and MDC/CCL22. Eotaxin-1 and MDC were particularly useful in distinguishing between the schizophrenia and HC groups, although they should not be regarded as diagnostic markers. The group difference in TARC levels decreased considerably after adjusting for age, gender, BMI, and smoking, suggesting that it was primarily related to demographic factors. Our
Role of the funding source
This study was supported in part by NIH grants 5R01MH094151-04 and 5T32 MH019934-21 (Jeste), UL1 RR031980 for the UCSD Clinical and Translational Research Institute, the VA Desert-Pacific Mental Illness Research Education and Clinical Center (Eyler), and UC San Diego Stein Institute for Research on Aging. Writing of this work is also supported in part by an NIH grant 1R01HL126056 (Hong).
Conflict of interest
None of the authors had any financial conflict of interest with the subject matter of this study.
Contributors
Dr. Hong wrote the first draft of the manuscript, performed literature searches, and conducted analyses. Drs. Lee and Martin performed literature searches and conducted analyses. Dr. Benchawanna Soontornniyomkij performed the assays. Dr. Virawudh Soontornniyomkij and Dr. Achim contributed to manuscript preparation. Mr. Reuter performed all statistical analyses. Dr. Irwin wrote sections of the manuscript. Drs. Eyler and Jeste designed the study and wrote the protocol. All the authors contributed
Acknowledgement
We thank Rebecca Daly for her considerable contributions to data management and analysis for the project.
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